tbuckley/cabot-search huggingface dataset:
PB1986: ADDITION OF CARFILZOMIB AS A THIRD AGENT IN LENALIDOMIDE-REFRACTORY MULTIPLE MYELOMA: SWITCHING FROM DOUBLET TO TRIPLET
Authors: C. Cerchione, D. Nappi, A. E. Pareto, S. Ronconi, D. Cangini, M. Ceccolini, G. Musuraca, L. Catalano, G. Martinelli
Journal: HemaSphere (2022)

Background: Carfilzomib is an epoxyketone proteasome inhibitor of secondgeneration, proved to be effective and safe in relapsed and refractory Multiple Myeloma (rrMM), in combination with dexamethasone or lenalidomide and dexamethasone. Aims: In this retrospective observational trial, it has been evaluated efficacy and safety of carfilzomib, in combination with lenalidomide-dexamethasone (KRD) as salvage regimen in patients with rrMM, refractory to lenalidomide, where lenalidomide-based regimens have no proven efficacy. Methods: 41 patients (23 M/18 F), with rrMM, median age at diagnosis 63.7years (r. 43-82), median age at start of treatment 67 years (r. 48-84)previously treated with several lines of treatments (median 3, r. 2-1),underwent to KRD regimen (ASPIRE trial schedule) for a median treatmentcycles of 8 (r 2-18). ISS was equally distributed, and all patients hadpreviously been treated with bortezomib and IMIDs, and were refractory to this agents. 61% (19/31) of them had undergone at least to a single ASCT. Results: According to IMWG criteria, after a median follow-up of 9 months (r.2-18), ORR was 68,2% (28/41: 9 CR, 12 VGPR, 7 PR) with 5 progressive diseases (PD) and 8 patients in stable disease (SD): this can be considered as an impressive result in this subset of rrMM patients, refractory to lenalidomide. In particular, for 11 patients, KRD was, after having achieved at least a PR, a bridge to second/third autologous SCT. Median time to response was 1.3 months (r.1-4), median OS from diagnosis was 62 months (r. 9-170), median OS from start of Carfilzomib was 11 months (r. 2-18). Carfilzomib was well tolerated, with grade 2 anemia in 39% (16/41) of patients,successfully managed by ESAs, without necessity of blood transfusions; 29%(12/41) grade 3-4 neutropenia (pegfilgrastim in primary prophylaxis wasgiven, no ospedalization was required, no septic shocks were observed); 34%(14/41) grade 2, 21% (9/41) grade 3 and 12% (5/41) grade 4 thrombocytopenia, without hemorrhagic events and transfusion-dependency. Moreover, it was observed pneumonia in 39% (16/41) of patients, treated by common antibiotic drugs and always solved. A cardiac monitoring was performed for all patients: hypertension (grade 2-3) in 34%(14/41) of patients; fatigue in 39% (16/31) of patients. Summary/Conclusion: Carfilzomib-Lenalidomide-Dexamethasone has shown significant efficacy in a particularly severe setting of patients, relapsed and refractory to all available therapeutic resources, also lenalidomide, and it could be considered as a bridge to a second autologous or allogenic SCT.
Abstract LB216: Pre-clinical characterization of NGM831, an ILT3 antagonist antibody for the treatment of solid tumors
Authors: Peirong Chen, Suzanne C. Crawley, Vicky Y. Lin, Varun Kapoor, Kevin J. Paavola, Hung-I Chen, Joshua S. Lichtman, Betty Li, Kalyani Mondal, Alan K. Kutach, Yan Wang, Daniel D. Kaplan, Julie M. Roda
Journal: Cancer Research (2022)

Abstract Suppressive myeloid cells inhibit antitumor immunity by preventing T cell responses. Immunoglobulin-like transcript 3 (ILT3, also known as LILRB4) is highly expressed on tumor-associated myeloid cells and promotes their suppressive phenotype. Our team recently identified fibronectin as a functional ligand for ILT3. The fibronectin-ILT3 interaction serves as a “stromal checkpoint” through which the extracellular matrix actively promotes myeloid cell suppression in the tumor microenvironment. We now report the pre-clinical characterization of NGM831, a humanized IgG1 (N297G) antibody that binds to ILT3 of human and cynomolgus monkey origin with high specificity and sub-nM affinity and blocks the interaction of ILT3 with both its reported ligands, fibronectin and ApoE. In a gene expression profiling experiment, treatment of tolerogenic dendritic cells with NGM831 in the presence of fibronectin decreased their expression of inhibitory and scavenger receptors (CD163, MRC1, MARCO, STAB1, LILRB2) and markers of dendritic cell immaturity (CD14, CD209, FOLR2) and increased their expression of genes involved in antigen presentation (TNFSF14, DCSTAMP, CD82, OLR1) and TH1 polarization (SPP1, TBX21), suggesting that these cells had been remodeled to a more stimulatory phenotype. Consistent with these observations, treatment of tolerogenic dendritic cells with NGM831 increased their production of pro-inflammatory cytokines in response to FcɣR ligation, restored their responsiveness to maturation stimuli such as lipopolysaccharide (LPS) and CD40 ligand (CD40L), and increased their production of chemokines that could induce the migration of other immune cells to sites of inflammation. In addition, NGM831 acted synergistically with pembrolizumab to increase the ability of dendritic cells to stimulate allogeneic T cells in mixed lymphocyte reactions. Taken together, these results demonstrate that NGM831 can block fibronectin-mediated immunosuppression and promote myeloid cell reprogramming. These data support the clinical development of the ILT3 antagonist antibody NGM831 alone and in combination with immune checkpoint blockade. NGM831 is expected to enter clinical trials for the treatment of advanced solid tumors in early 2022. Citation Format: Peirong Chen, Suzanne C. Crawley, Vicky Y. Lin, Varun Kapoor, Kevin J. Paavola, Hung-I Chen, Joshua S. Lichtman, Betty Li, Kalyani Mondal, Alan K. Kutach, Yan Wang, Daniel D. Kaplan, Julie M. Roda. Pre-clinical characterization of NGM831, an ILT3 antagonist antibody for the treatment of solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB216.
Abstract SY30-01: Translational issues in lung cancer disparities: A vision for cancer equity
Authors: Chanita Hughes-Halbert
Journal: Cancer Research (2022)

Abstract Lung cancer continues to be one of the leading causes of racial disparities in cancer morbidity and mortality among adults in the United States. Over the past 20 years, efforts to address disparities in lung cancer outcomes have focused on describing racial/ethnic differences in smoking behaviors and cessation outcomes. Other research has compared racial/ethnic groups in psychosocial and geographic risk factors for smoking and barriers to cessation; self-reported perceptions of stress and neighborhood deprivation have emerged as critical determinants of persistent tobacco use and predictors of relapse in disparity populations. Considerable investments have also been made to develop novel approaches for detecting lung cancer early and therapeutic strategies for treating this disease; lung cancer screening with LDCT now has a Grade B recommendation from the US Preventive Services Task Force and screening guidelines have been revised recently to be better aligned with the smoking behaviors and disease risk profiles among smokers from disparity populations. The demonstrated ability of LDCT to reduce lung cancer mortality is a significant clinical and public health advancement because it is the only evidence-based approach for detecting lung cancer at an early stage when treatment is most likely to be curative. However, several studies have demonstrated that patients from disparity populations have reduced uptake of cancer control strategies such as LDCT because of unmet social needs and risk factors; thus, revising lung cancer screening guidelines to be more inclusive may be necessary but not sufficient for improving access among disparity populations. The purpose of this presentation is to describe the goals and objectives for translational studies that are now being conducted to enhance equity in lung cancer outcomes among disparity populations and to identify priorities for future research in lung cancer equity. Citation Format: Chanita Hughes-Halbert. Translational issues in lung cancer disparities: A vision for cancer equity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr SY30-01.
P1191: ANALYSIS OF PERIPHERAL NEUROPATHY USING CLINICIAN- AND PATIENT-REPORTED OUTCOMES IN THE POLARIX STUDY
Authors: M. Trněný, L. Fogliatto, F. Gardner, I. Flinn, J.-F. Larouche, C. Haioun, M. Canales, H. Goto, R. Hajek, G. Salles, J. Qiu, A. Campinha-Bacote, M. Yan, R. Kothari, G. Man, D. Sahin, J. Hirata, C. Lee, H. Tilly, C. Flowers
Journal: HemaSphere (2022)

Background: Peripheral neuropathy (PN) is an identified risk of anti-microtubule agents, including polatuzumab vedotin and vincristine. POLARIX (NCT03274492), a Phase III randomized, double-blind, placebo-controlled study comparing Pola-R-CHP with R-CHOP, demonstrated improved progression-free survival (PFS) with Pola-R-CHP (Tilly et al. NEJM 2022). Aims: To evaluate the impact of Pola-R-CHP vs R-CHOP on PN using clinician- and patient-reported outcomes (ClinRO and PRO) data. Methods: Patients with previously untreated diffuse large B-cell lymphoma (DLBCL) received Pola-R-CHP or R-CHOP. All patients provided informed consent. Pola-R-CHP is an investigational combination. ClinRO data were based on PN grading according to the NCI CTCAE v4.0. PRO data were generated from assessment of patient-reported PN symptoms at baseline and Day 1 of each cycle using the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group – Neurotoxicity (FACT-GOG/NTX) subscale, ranging from 0–44, with higher scores representing lower levels of PN (minimal clinically important difference: 1.38–3.68 [Cheng et al. Health Qual Life Outcomes 2020]). Results: At baseline, ClinRO and PRO symptom scores showed low PN burden (Table). Overall incidence of PN was comparable between treatment arms (Pola-R-CHP: 52.9%; R-CHOP: 53.9%); most events were grade 1, and incidence of grade 2 (Pola-R-CHP: 12.2%; R-CHOP: 15.5%) and grade 3 (Pola-R-CHP: 1.6%; R-CHOP: 1.1%) events were comparable between treatment arms. FACT-GOG/NTX survey completion was high in both arms (96% at baseline; >80% at other timepoints). When evaluated by cycle, ClinRO and PRO demonstrated that more patients experienced earlier onset PN with R-CHOP than with Pola-R-CHP (Table), with ~10% more R-CHOP- than Pola-R-CHP-treated patients having clinician-reported PN in Cycle (C) 2–5, and a ~+1-point difference (i.e. fewer symptoms) in PRO symptom scores in C3–6 with Pola-R-CHP vs R-CHOP; by C8+, and during follow up, rates and symptoms of PN were similar. PN symptoms resulted in fewer dose reductions (3.9% vs 8.2%) and drug discontinuations (0.7% vs 2.1%) with Pola-R-CHP vs R-CHOP. Duration of PN was similar for both treatments. Image:Summary/Conclusion: In the POLARIX study, Pola-R-CHP did not result in different rates or severity of PN vs R-CHOP. According to ClinRO and PRO data, PN occurred later following initial exposure to Pola-R-CHP than to R-CHOP, and there were fewer dose modifications with Pola-R-CHP than with R-CHOP. Overall, the risk of PN was manageable.
PB1877: ADJUSTING SURVIVAL DATA FOR TREATMENT CROSSOVER IN THE ELEVATE-TN TRIAL BY USING A HISTORICAL COHORT OF PATIENTS TREATED WITH CHEMOIMMUNOTHERAPY IN FRONT-LINE CHRONIC LYMPHOCYTIC LEUKEMIA
Authors: P. Gaitonde, B. Liljas, B. Shaw, P. Miranda
Journal: HemaSphere (2022)

Background: Acalabrutinib (A) is a next-generation Bruton tyrosine kinase inhibitor (BTKi) approved for chronic lymphocytic leukemia (CLL) treatment. ELEVATE-TN trial interim data (~47 months median follow-up [FU]) did not show survival benefit for A±obinutuzumab (O) versus chlorambucil+obinutuzumab (C+O) despite significantly superior progression-free survival (PFS). One explanation is C+O-to-A patient crossover (39%), which may have provided added overall survival (OS) benefit to the C+O arm. Aims: We evaluated OS by adjusting for crossover using a historical C+O cohort. Methods: The CLL11 trial demonstrated superior PFS and OS for C+O versus C and C+rituximab in first-line CLL prior to BTKi availability. Therefore, OS data for BTKi-naive C+O patients were digitized and compared with A±O from ELEVATE-TN. Individual patient datasets were used to plot Kaplan-Meier (KM) curves and calculate hazard ratios (HR) using Cox regression in R software. To validate our hypothesis (impact of crossovers on relative survival benefit), we compared 28-month FU data from ELEVATE-TN, where we observed lower OS HRs (non-significant) to CLL-11 data until that time period. The CLL11 and ELEVATE-TN trials enrolled patients with similar baseline characteristics; however, this analysis did not account for within-trial heterogeneity. Results: There was a statistically significant reduction in risk of death with all 3 ELEVATE-TN treatments (47-month FU data) versus CLL-11 C+O: A+O versus C+OCLL11 (HR=0.23 [95% CI=0.12-0.42, p<0.001]); A versus C+OCLL11 (HR=0.43 [95% CI=0.27-0.70, p<0.001]); C+O versus C+OCLL11 (HR=0.44 [95% CI=0.27-0.71, p<0.001]). In the additional analysis with 28-month FU data, comparing ELEVATE-TN arms with C+O from CLL-11, KM curves for C+O overlapped (HR=0.79 [95% CI=0.42-1.47], p>0.05), indicating no difference. However, HRs for A+O versus C+OCLL11 (HR=0.39 [95% CI=0.18-0.84], p=0.02) and for A versus C+OCLL11 (HR=0.48 [95% CI=0.24-0.99], p<0.05) were statistically significant. Summary/Conclusion: The non-statistically significant OS for A±O versus C+O was likely due to treatment crossover. Conducting a treatment-switching analyses was challenging due to immature OS data; however, this analysis supports the hypothesis that crossover to A bolstered ELEVATE-TN C+O OS.
PB2348: THE PATIENT’S PERSPECTIVE ON CLNICAL TRIALS: RESULTS FROM A REGIONAL SURVEY IN HAEMATOLOGICAL CENTERS IN ANTWERP
Authors: B. Heyrman, S. Meers, A. Van De Velde, S. Anguille
Journal: HemaSphere (2022)

Background: Clinical trials are a prerequisite for medical progress. Unfortunately, only a small proportion of patients participates in clinical studies. Implementation of a digital informed consent form (ICF) is another possible barrier in the process of trial inclusion Aims: Primary objective was to collect information on the attitude and knowledge on clinical trials in haematological patients. Secondary objective was to explore influenceable variables in the decision making process. Methods: We conducted an anonymous survey in haematological patients during a fixed period of 6 months in 4 hospitals in the province of Antwerp, Belgium. Patients were invited to participate via flyers that were handed out by accredited haematologists or had the possibility to fill out the survey on site on tablets provided in the hospitals. The survey was built by the authors in Qualtrics® which was used for data collection and approved by the ethical committee of the University Hospital Antwerp. Results: During the 6-month recruitment period, 420 patients filled out the survey, 219 female, 187 male, 14 patients did not answer this question. More than half of the patients (56 %) was over 60 years old. Half of the patients (50.8%) was not or totally not aware of clinical trial concepts, yet 87.9% indicated to have a positive feeling about clinical trials. Most patients (87.3%) trusted in the safety of clinical trials. The majority of patients (67,0%) was more or less willing to participate in a clinical trial when offered (24% previously or actively participated in a clinical trial). A significant relation in willingness to trial-participation and trial-knowledge (p<0.001) and doctor-patient relationship (p=0.007) was noted. Age was not a statistical significant variable for willingness to participate (p=0.64). A large portion (21.0%) was not willing to go to another hospital for trial participation, or only in case there was no other possible treatment (20.4%). A greater part (79.9%) indicated to prefer to know the results of the study following study closure. In case of study participation, information will mainly be obtained from the general practitioner (26.4%) and treating haematologist (39.9%). In the group of trial patients, 73.1% was satisfied with the information in the ICF, 85.9% indicated to have had sufficient amount of time to pose questions and 76.1% would advise study participation to others. Only 24.5% of patients above 60 years indicated to be willing to use a digital ICF procedure vs 57,0% in the group younger than 60 (p<0.001). Summary/Conclusion: Our results are in line with other publications that the majority of patients is willing to participate in a clinical trial when offered. Implementation of a digital ICF is not preferred by the majority of our patients, who are mainly 60 years or older. Investment in patient information and patient-doctor relation is a key factor to motivate patients for trial participation.
Global impact of the first year of COVID-19 vaccination: a mathematical modelling study
Authors: Oliver J Watson, Gregory Barnsley, Jaspreet Toor, Alexandra B Hogan, Peter Winskill, Azra C Ghani
Journal: The Lancet Infectious Diseases (2022)

The first COVID-19 vaccine outside a clinical trial setting was administered on Dec 8, 2020. To ensure global vaccine equity, vaccine targets were set by the COVID-19 Vaccines Global Access (COVAX) Facility and WHO. However, due to vaccine shortfalls, these targets were not achieved by the end of 2021. We aimed to quantify the global impact of the first year of COVID-19 vaccination programmes.A mathematical model of COVID-19 transmission and vaccination was separately fit to reported COVID-19 mortality and all-cause excess mortality in 185 countries and territories. The impact of COVID-19 vaccination programmes was determined by estimating the additional lives lost if no vaccines had been distributed. We also estimated the additional deaths that would have been averted had the vaccination coverage targets of 20% set by COVAX and 40% set by WHO been achieved by the end of 2021.Based on official reported COVID-19 deaths, we estimated that vaccinations prevented 14·4 million (95% credible interval [Crl] 13·7-15·9) deaths from COVID-19 in 185 countries and territories between Dec 8, 2020, and Dec 8, 2021. This estimate rose to 19·8 million (95% Crl 19·1-20·4) deaths from COVID-19 averted when we used excess deaths as an estimate of the true extent of the pandemic, representing a global reduction of 63% in total deaths (19·8 million of 31·4 million) during the first year of COVID-19 vaccination. In COVAX Advance Market Commitment countries, we estimated that 41% of excess mortality (7·4 million [95% Crl 6·8-7·7] of 17·9 million deaths) was averted. In low-income countries, we estimated that an additional 45% (95% CrI 42-49) of deaths could have been averted had the 20% vaccination coverage target set by COVAX been met by each country, and that an additional 111% (105-118) of deaths could have been averted had the 40% target set by WHO been met by each country by the end of 2021.COVID-19 vaccination has substantially altered the course of the pandemic, saving tens of millions of lives globally. However, inadequate access to vaccines in low-income countries has limited the impact in these settings, reinforcing the need for global vaccine equity and coverage.Schmidt Science Fellowship in partnership with the Rhodes Trust; WHO; UK Medical Research Council; Gavi, the Vaccine Alliance; Bill & Melinda Gates Foundation; National Institute for Health Research; and Community Jameel.
Astrocytic urea cycle detoxifies Aβ-derived ammonia while impairing memory in Alzheimer’s disease
Authors: Yeon Ha Ju, Mridula Bhalla, Seung Jae Hyeon, Ju Eun Oh, Seonguk Yoo, Uikyu Chae, Jea Kwon, Wuhyun Koh, Jiwoon Lim, Yongmin Mason Park, Junghee Lee, Il-Joo Cho, Hyunbeom Lee, Hoon Ryu, C. Justin Lee
Journal: Cell Metabolism (2022)
PB2175: TRYPAN BLUE AND FLOW CYTOMETRY CELL VIABILITY TESTING OF PACKED OR DILUTED CRYOPRESERVED AT -80ºC HEMATOPOIETIC STEM CELLS SHOW SIMILAR RESULTS
Authors: I. Tonev, S. Simeonov, M. Ilieva, M. Muhtarova, R. Vladimirova, N. Andreinski, T. Yancheva, M. Guenova, M. MIncheff
Journal: HemaSphere (2022)

Background: Trypan blue exclusion and flow cytometry were compared for testing of cell viability of hemopoietic stem cells (HSCs) cryopreserved at -80ºC. Stem cells were frozen and stored with 5% final DMSO concentration with different degree of cell packing. Aims: We wanted to evaluate the difference in viability results with folw cytometry and trypan blue exclusion with different degree of cell packing. Methods: We analyzed 47 samples stored at -80ºС in a cryoprotectant solution with final concentrations of 5% DMSO, 3.6% hydroxyethyl starch (HES 450 000 mw) and 3% of human serum albumin. The cell concentration in the frozen suspension ranged between 69х106/ml and 665х106/ml (median 310,25х106/ml). The cell viability was tested simultaneously by trypan blue exclusion test and by flow cytometry with 7 -aminoactinomycin D (7-AAD) without lysing solution. Results: Both viability tests gave similar results. When tested by trypan blue, the viability was 95,5% (80-99%), and by flow cytometry was 95,92% (89,1-98,4%). The additional statistical Spearman's Rho analysis does not show statistically significant correlation between viability results, performed with either test, and the degree of cell packing. Summary/Conclusion: Flow cytometry and trypan blue tests show similar viability results. Since trypan blue testing is well established, has lower cost, and can be performed faster, we accepted it as a routine for our further analyses of cell viability of packed prior to freezing stem cell concentrates. HSC viability after storage at -80ºС with 5% final DMSO concentration is very good and is not affected by higher cell packing thus allowing the reduction of infused DMSO and the side effects (cardiac, neurologic, respiratory, etc.) during transplantation.
Early food intervention and skin emollients to prevent food allergy in young children (PreventADALL): a factorial, multicentre, cluster-randomised trial
Authors: Håvard Ove Skjerven, Anine Lie, Riyas Vettukattil, Eva Maria Rehbinder, Marissa LeBlanc, Anna Asarnoj, Kai-Håkon Carlsen, Åshild Wik Despriee, Martin Färdig, Sabina Wärnberg Gerdin, Berit Granum, Hrefna Katrín Gudmundsdóttir, Guttorm Haugen, Gunilla Hedlin, Geir Håland, Christine Monceyron Jonassen, Linn Landrø, Caroline-Aleksi Olsson Mägi, Inge Christoffer Olsen, Knut Rudi, Carina Madelen Saunders, Marius Kurås Skram, Anne Cathrine Staff, Cilla Söderhäll, Sandra G Tedner, Sigve Aadalen, Hilde Aaneland, Björn Nordlund, Karin C Lødrup Carlsen
Journal: The Lancet (2022)